NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys) AND Bethlem myopathy 1A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000817700.10

Allele description [Variation Report for NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys)]

NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys)

Gene:

COL6A3:collagen type VI alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.3

Genomic location:

Preferred name:

NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys)

Other names:

NM_004369.3(COL6A3):c.6199G>A; p.Glu2067Lys

HGVS:

NC_000002.12:g.237361132C>T
NG_008676.1:g.58076G>A
NM_004369.4:c.6199G>AMANE SELECT
NM_057166.5:c.4378G>A
NM_057167.4:c.5581G>A
NP_004360.2:p.Glu2067Lys
NP_004360.2:p.Glu2067Lys
NP_476507.3:p.Glu1460Lys
NP_476508.2:p.Glu1861Lys
LRG_473t1:c.6199G>A
LRG_473:g.58076G>A
LRG_473p1:p.Glu2067Lys
NC_000002.11:g.238269775C>T
NM_004369.3:c.6199G>A
NM_004369.4:c.6199G>A

Protein change:

E1460K

Links:

dbSNP: rs760446904

NCBI 1000 Genomes Browser:

rs760446904

Molecular consequence:

NM_004369.4:c.6199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_057166.5:c.4378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_057167.4:c.5581G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Bethlem myopathy 1A
Synonyms:: Myopathy, benign congenital, with contractures; Bethlem myopathy 1
Identifiers:: MONDO: MONDO:0024530; MedGen: CN029274; Orphanet: 610; OMIM: 158810

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000958278	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24271325, 26436962, 30564623, 28492532
SCV001976753	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000958278

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001976753

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 10, 2021)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Natural history of pulmonary function in collagen VI-related myopathies.

Foley AR, Quijano-Roy S, Collins J, Straub V, McCallum M, Deconinck N, Mercuri E, Pane M, D'Amico A, Bertini E, North K, Ryan MM, Richard P, Allamand V, Hicks D, Lamandé S, Hu Y, Gualandi F, Auh S, Muntoni F, Bönnemann CG.

Brain. 2013 Dec;136(Pt 12):3625-33. doi: 10.1093/brain/awt284. Epub 2013 Nov 22.

PubMed [citation]

PMID:: 24271325
PMCID:: PMC3859224

Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned.

Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O'Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF.

JAMA Neurol. 2015 Dec;72(12):1424-32. doi: 10.1001/jamaneurol.2015.2274.

PubMed [citation]

PMID:: 26436962

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000958278.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2067 of the COL6A3 protein (p.Glu2067Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant Bethlem myopathy or limb-girdle muscular dystrophy (PMID: 24271325, 26436962, 30564623; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 284554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL6A3 protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976753.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS2, PM1, PM2, PP3, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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